1. Field of the Invention
This invention relates to biologically active vitamin D5 compounds. More specifically, this invention relates to a series of novel D5 compounds, including the compound 1α-Hydroxyvitamin D5, their synthesis and their use in cancer prevention and therapy.
2. Description of the Related Art
Vitamin D is a secosteroid and is classified as a hormone within the steroid hormone family. Vitamin D's are differentiated on the basis of side-chain chemical structures into different series, e.g., D2, D3, D4, D5, and D6. To date, attention has been focused almost exclusively on the vitamin D3 series of compounds. In its biological form, vitamin D3 is inactive until it is metabolized to 1α, 25-dihydroxyvitamin D3 [1α, 25 (OH)2D3], the natural metabolite. The inactive 24-hydroxy form of the hormone is excreted from the body. The active metabolite 1α, 25 (OH)2D3 has been shown to suppress the growth in vitro of many neoplastic cells, including breast cancer cells. In addition, treatment of colon cancer cells and leukemia cells with 1α, 25 (OH)2D3 results in a reduction in the growth rate of these cells.
One of the limiting factors in the successful use of vitamin D3 in cancer prevention or cancer therapy is its calcemic activity, i.e., the potentially fatal build-up of calcium in the body. The concentrations of vitamin D3 required to suppress growth of neoplastic cells can cause hypercalcemia and death. Therefore, in recent years, numerous analogues of vitamin D have been synthesized that possess reduced calcemic activity without compromising their antiproliferative activity. The differences in structures of these new compounds arise mostly from modifications in the A and D rings and side chain of the vitamin.
We have synthesized the novel compound 1α-Hydroxyvitamin D5 [1α(OH)D5] and compared its effectiveness as a chemopreventative to the active metabolite of vitamin D3. We have also attempted to determine the possible mechanism of such chemopreventative action by studying the expression of vitamin D receptors (VDRs) and transforming growth factor-β(TGF-β) in normal mammary epithelial cells.